Summary

Ectopic adrenocorticotropic hormone (ACTH) secretion is responsible for 5–15% of Cushing’s syndrome (CS). Neuroendocrine tumor (NET) is a common cause of ectopic ACTH syndrome (EAS). However, primary renal NET is exceedingly rare. Fewer than 100 cases have been reported and only a few cases presented with CS. Because of its rarity and lack of long-term follow-up data, clinical manifestations, biological behavior and prognosis are not well understood. Here, we report the case of a 51-year-old man who presented with clinical and laboratory findings compatible with EAS. CT scan revealed a lesion of uncertain nature at the lower pole of the left kidney. Octreotide scan found a filling defect at the lower pole of left kidney. It was difficult to determine if this finding was the true etiology or an incidental finding. Unfortunately, the patient’s clinical status rapidly deteriorated with limited medical treatment. The patient underwent left nephrectomy and left adrenalectomy. Histopathological examination confirmed NET with oncocytic features. Immunohistochemistry staining was positive for ACTH. The patient’s condition gradually improved. Additionally, glucocorticoid replacement was required only 6 months during a gradual recovery of hypothalamic pituitary adrenal axis achieved approximately three years after tumor removal. Although extremely rare, primary renal NET should be considered as a cause of EAS particularly in a patient with rapid clinical deterioration. Thorough investigation, early diagnosis and careful management are crucial to reduce morbidity and mortality.

Learning points

• Primary renal NET is an extremely rare cause of ectopic ACTH syndrome.

• Ectopic ACTH syndrome has a rapid onset with severe clinical manifestations. In this case, the patient’s condition deteriorated rapidly, resulting from severe hypercortisolism. Resection of the tumor is the most effective treatment.

• Localization of ectopic ACTH-secreting tumors is very challenging. Multimodality imaging including CT, MRI, octreotide scan, and positron emission tomography plays a crucial role in identifying the tumors. However, each imaging modality has limitations.

Summary

Comorbidities are a risk factor for patients with COVID-19 and the mechanisms of disease remain unclear. The aim of this paper is to present a case report of an COVID-19 patient with severe hypocalcaemia. This is a report of an 81-year-old female, suffered from myalgia and fatigue for more than 3–4 weeks. Fever and cough appear 2 days before she presented to the emergency room. On physical examination, she was febrile with a temperature of 38.8°C, accompanied by cough, sore throat, headache, fatigue, and muscle ache. Her past medical history was remarkable with no chronic disease. She had lymphopenia. Laboratory test revealed moderate liver dysfunction, hypoalbuminemia, and severe hypocalcaemia (serum corrected calcium level: 5.7  mg/dL). Parathyroid hormone (PTH) was 107.9 pg/mL (range: 15–65) and 25(OH)2D levels was 4.5 ng/mL (range: 25–80). Chest CT scan detected peripheral ground-glass opacity. Throat swab for coronavirus by RT-PCR assay tested positive for the virus. She was treated with lopinavir/ritonavir, third generation cephalosporin, anticoagulant, daily high-dose calcium acetate, vitamin D₃, fresh frozen plasma and oxygen therapy. She was discharged after two negative throat swab tests for coronavirus by conventional RT-PCR.

Learning points:

• Comorbidities are a risk factor for patients with COVID-19.

• Laboratory findings are unspecific in COVID-19 patients; laboratory abnormalities include lymphopenia, elevated of LDH, CPK and the inflammatory markers, such as C reactive protein, ferritinemia and the erythrocyte sedimentation rate.

• In addition to inflammatory markers, in COVID-19 patients it is crucial to check the level of vitamin D and calcium.

• There may be a correlation between vitamin D deficiency and the severity of COVID-19 disease.

Summary

We present a 60-year-old woman who underwent successful surgical resection (partial pancreatectomy) for a low grade non-functioning pancreatic neuroendocrine tumour (pNET), with no biochemical or radiological features of recurrence on follow-up visits for 5 years. Fourteen years after the initial surgery, she developed spontaneous severe hypoglycaemic episodes which required hospitalisation, with subsequent investigations confirming the diagnosis of a metastatic insulin-secreting pNET (insulinoma). Medical management of her severe spontaneous hypoglycaemic episodes remained challenging, despite optimum use of diazoxide and somatostatin analogue therapy. Based on a discussion at the regional neuroendocrine tumour multidisciplinary team meeting, she underwent an elective hepatic trans-arterial embolization which was unfortunately unsuccessful. She ended up requiring an emergency right hemihepatectomy and left retroperitoneal mass resection which finally stabilised her clinical condition.

Learning points:

• Ours is only the seventh case report of a previously benign pNET presenting as a functional insulin secreting metastatic tumour. However, it is the first case report, in which the metastatic functional pNET presented after such a long hiatus (14 years).

• There is currently no clear consensus regarding the length of follow-up of non-functional pNET which are deemed cured post-surgical resection, with most guidelines advocating a median follow up of 5 years (1). The delayed presentation in our case suggests additional considerations should be made regarding optimal post-operative surveillance duration based on the age of the patient, location of the tumour, lymph node spread and Ki-67 index.

• Hepatic artery embolization and/or partial hepatectomy remains a treatment option for pNET patients with significant hepatic metastasis.

Summary

Familial hypocalciuric hypercalcaemia (FHH) is a dominantly inherited, lifelong benign disorder characterised by asymptomatic hypercalcaemia, relative hypocalciuria and variable parathyroid hormone levels. It is caused by loss-of-function pathogenic variants in the calcium-sensing receptor (CASR) gene. Primary hyperparathyroidism (PHPT) is characterised by variable hypercalcaemia in the context of non-suppressed parathyroid hormone levels. Unlike patients with FHH, patients with severe hypercalcaemia due to PHPT are usually symptomatic and are at risk of end-organ damage affecting the kidneys, bone, heart, gastrointestinal system and CNS. Surgical resection of the offending parathyroid gland(s) is the treatment of choice for PHPT, while dietary adjustment and reassurance is the mainstay of management for patients with FHH. The occurrence of both FHH and primary hyperparathyroidism (PHPT) in the same patient has been described. We report an interesting case of FHH due to a novel CASR variant confirmed in a mother and her two daughters and the possible coexistence of FHH and PHPT in the mother, highlighting the challenges involved in diagnosis and management.

Learning points:

• Familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (PHPT) can coexist in the same patient.

• Urinary calcium creatinine clearance ratio can play a role in distinguishing between PHPT and FHH.

• Genetic testing should be considered in managing patients with PHPT and FHH where the benefit may extend to the wider family.

• Family segregation studies can play an important role in the reclassification of variants of uncertain significance.

• Parathyroidectomy has no benefit in patients with FHH and therefore, it is important to exclude FHH prior to considering surgery.

• For patients with coexisting FHH and PHPT, parathyroidectomy will reduce the risk of complications from the severe hypercalcaemia associated with PHPT.

Summary

Type B insulin resistance syndrome (TBIR) is characterised by the rapid onset of severe insulin resistance due to circulating anti-insulin receptor antibodies (AIRAs). Widespread acanthosis nigricans is normally seen, and co-occurrence with other autoimmune diseases is common. We report a 27-year-old Caucasian man with psoriasis and connective tissue disease who presented with unexplained rapid weight loss, severe acanthosis nigricans, and hyperglycaemia punctuated by fasting hypoglycaemia. Severe insulin resistance was confirmed by hyperinsulinaemic euglycaemic clamping, and immunoprecipitation assay demonstrated AIRAs, confirming TBIR. Treatment with corticosteroids, metformin and hydroxychloroquine allowed withdrawal of insulin therapy, with stabilisation of glycaemia and diminished signs of insulin resistance; however, morning fasting hypoglycaemic episodes persisted. Over three years of follow-up, metabolic control remained satisfactory on a regimen of metformin, hydroxychloroquine and methotrexate; however, psoriatic arthritis developed. This case illustrates TBIR as a rare but severe form of acquired insulin resistance and describes an effective multidisciplinary approach to treatment.

Learning points:

• We describe an unusual case of type B insulin resistance syndrome (TBIR) in association with mixed connective tissue disease and psoriasis.

• Clinical evidence of severe insulin resistance was corroborated by euglycaemic hyperinsulinaemic clamp, and anti-insulin receptor autoantibodies were confirmed by immunoprecipitation assay.

• Treatment with metformin, hydroxychloroquine and methotrexate ameliorated extreme insulin resistance.

Summary

Insulin autoimmune syndrome (Hirata’s disease) is a disorder caused by development of autoantibodies to insulin and manifested by hypoglycaemic syndrome. The overwhelming majority of physicians do not include it in the differential diagnosis of hypoglycaemic states because of a misconception of an extremely low prevalence of this condition. This results in unnecessary drug therapy and unjustified surgical interventions in patients that otherwise would be successfully treated conservatively. This disease is strongly associated with certain alleles of the HLA gene. In most cases, this condition develops in predisposed individuals taking drugs containing sulfhydryl groups. Formation of autoantibodies to insulin may be observed in patients with other autoimmune disorders, as well as in those with multiple myeloma or monoclonal gammopathy of undetermined significance. This paper presents the first Russian case report of insulin autoimmune syndrome in an adult patient.

Learning points:

• Insulin autoimmune syndrome, Hirata’s disease, anti-insulin antibodies, and hypoglycaemia.

Summary

We describe the case of a 56 year-old woman with the almost simultaneous appearance of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and a carotid body paraganglioma. Of interest, 6 years earlier, the patient underwent total thyroidectomy due to papillary thyroid carcinoma and, in the meantime, she was submitted to mastectomy to treat an invasive ductal carcinoma of the breast. In order to explain these lesions, an extensive genetic study was performed. Results showed positivity for the presence of the tumor suppressor gene PALB2, whose presence had already been detected in a niece with breast cancer. The patient underwent different procedures to treat the lesions and currently she is symptom-free over 2 years of follow-up.

Learning points:

• The presence of two rare neoplasms in a single person should raise the suspicion of a common etiology.

• To the best of our knowledge, this is the first case that shows the coexistence of DIPNECH and paraganglioma.

• The contribution of the PALB2 gene in the etiology of these rare neoplasms is a possibility.

Summary

Familial hypomagnesemia with secondary hypocalcemia (FHSH) is a rare autosomal recessive disorder (OMIM# 602014) characterized by profound hypomagnesemia associated with hypocalcemia. It is caused by mutations in the gene encoding transient receptor potential cation channel member 6 (TRPM6). It usually presents with neurological symptoms in the first months of life. We report a case of a neonate presenting with recurrent seizures and severe hypomagnesemia. The genetic testing revealed a novel variant in the TRPM6 gene. The patient has been treated with high-dose magnesium supplementation, remaining asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to prevent irreversible neurological damage.

Learning points:

• Loss-of-function mutations of TRPM6 are associated with FHSH.

• FHSH should be considered in any child with refractory hypocalcemic seizures, especially in cases with serum magnesium levels as low as 0.2 mM.

• Normocalcemia and relief of clinical symptoms can be assured by administration of high doses of magnesium.

• Untreated, the disorder may be fatal or may result in irreversible neurological damage.

Summary

A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the left lobe, was inhomogeneously hypoechoic, with irregular margins, macrocalcifications and intranodular vascularization. Fine-needle aspiration biopsy (FNAB) was performed. The cytological diagnosis was TIR 2, benign, according to the 2013 Italian thyroid cytology classification system. Moderately high serum calcitonin (s-Ct) (61.5 pg/mL, n.r. 0–7.5) and normal CEA were detected. The Ct level in FNAB wash-out fluid (Ct-FNAB) was 1450 pg/mL. Based on s-Ct and Ct-FNAB levels, patient underwent total thyroidectomy. Macroscopically, a dominant circumscribed nodule of 2 ecm was described; the histological and immunohistochemical features identified medullary thyroid carcinoma (MTC) with paraganglioma (PG)-like pattern positive for Ct, CEA and chromogranin and negative for S-100 sustentacular cells (SC). Moreover, papillary carcinoma of 3 mm in the right lobe was also associated. No areas of hyperaccumulation of the tracer were documented at Ga68 PET/CT. No RET-proto-oncogene mutations were found. Post-surgery s-Ct levels were within normal range (4 pg/mL). Two years after thyroidectomy, the patient is still disease-free. We reported a case of sporadic and rare variant of MTC: this is the ninth described case of PG-like MTC. In this case, cytologically benign, the clinical suspicion arose from high Ct values at FNAB wash-out fluid. Even if clinical behavior of this variant seems indolent, additional studies are necessary to understand prognoses and predictive factors.

Learning points:

• Several unusual histological variants of medullary thyroid carcinoma (MTC) have been described such as spindle cell, giant cell, clear cell, melanotic, squamous, angiosarcoma-like variants; even rarer is the paraganglioma (PG)-like pattern.

• We here describe a case of medullary PG-like thyroid carcinoma in a 74-year-old man. This is a rare histological variant of MTC hardly diagnosed by cytology, since immunohistochemical investigations are necessary.

• Measurement of calcitonin both in serum and in wash-out fluid from fine-needle aspiration could be an additional tool for an early and non-invasive identification of these variants.

Summary

Patients treated with immunosuppressive drugs, especially methotrexate (MTX), rarely develop lymphoproliferative disorders (LPDs), known as MTX-related LPD (MTX–LPD). The primary site of MTX–LPD is often extranodal. This is the first reported case of MTX–LPD in the pituitary. A 65-year-old woman was admitted to our hospital with symptoms of oculomotor nerve palsy and multiple subcutaneous nodules. She had been treated with MTX for 11 years for rheumatoid arthritis. Computed tomography showed multiple masses in the orbit, sinuses, lung fields, anterior mediastinum, kidney, and subcutaneous tissue. Brain magnetic resonance imaging revealed a sellar mass. She was diagnosed with hypopituitarism and central diabetes insipidus based on endocrine examination. Although pituitary biopsy could not be performed, we concluded that the pituitary lesion was from MTX–LPD, similar to the lesions in the sinuses, anterior mediastinum, and subcutaneous tissue, which showed polymorphic LPD on biopsy. MTX was discontinued, and methylprednisolone was administered to improve the neurologic symptoms. After several weeks, there was marked improvement of all lesions, including the pituitary lesion, but the pituitary function did not improve. When pituitary lesions are caused by MTX–LPD, the possibility of anterior hypopituitarism and central diabetes insipidus needs to be considered. Further studies are needed to investigate the effectiveness of early diagnosis and treatment of MTX–LPD in restoring pituitary dysfunction.

Learning points

• Pituitary lesions from MTX–LPD may cause hypopituitarism and central diabetes insipidus.

• Pituitary metastasis of malignant lymphoma and primary pituitary lymphoma, which have the same tissue types with MTX–LPD, have poor prognosis, but the lesions of MTX–LPD can regress only after MTX discontinuation.

• In cases of pituitary lesions alone, a diagnosis of MTX–LPD may be difficult, unless pituitary biopsy is performed. This possibility should be considered in patients treated with immunosuppressive drugs.

• Pituitary hypofunction and diabetes insipidus may persist, even after regression of the lesions on imaging due to MTX discontinuation.